A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) - DREAMM 5.

Study Identifier:
208887
CT.gov Identifier:
NCT04126200
EudraCT Identifier:
2019-001138-32
EU Trial (CTIS) Number:
2023-509550-55-00
Study Contact Information:
N/A
Recruitment Complete

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Study Summary

To evaluate the effects of GSK'916 (belantamab mafodotin) in combination with other anti-cancer drugs in participants with relapsed/refractory multiple myeloma (RRMM).

DE phase: To identify a recommended phase 2 dose (RP2D) for each partner, as well as efficacy of each combination

CE phase: To evaluate the clinical activity of the combinations in comparison to monotherapy in additional participants with RRMM.

Dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N

Cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm.

To evaluate the safety, tolerability and preliminary efficacy of nirogacestat in combination with belantamab mafodotin in patients with relapsed or refractory multiple myeloma.

To identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only)

To determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved belamaf schedule (single agent dose 2.5 mg/kg Q3W) in patients with RRMM which showed a 31% overall response rate (ORR) and 44.5% Gr3/4 keratopathy (BLENREP US prescribing information).

B-cell maturation antigen (BCMA) is a target present on tumor cells in patients with multiple myeloma. Belantamab mafodotin (GSK2857916) is an antibody-drug conjugate (ADC) containing a humanized anti-BCMA monoclonal antibody (mAb). This is a platform study designed to evaluate the efficacy of belantamab mafodotin in combination with other anticancer drugs in patients with relapsed/refractory multiple myeloma. This platform study will evaluate multiple combinations of therapies simultaneously as substudies using a single master protocol.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Multiple Myeloma
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Belantamab mafodotin+GSK3174998 dose exploration (Sub-study 1)Drug: Belantamab mafodotin
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruitment Complete

    Requirements information
    Inclusion criteria
    • Participant must be 18 years of age inclusive or older, at the time of signing the informed consent.
    • Participants must have histologically or cytologically confirmed diagnosis of Multiple Myeloma (MM), as defined by the IMWG.
    • Participants having at least 3 prior lines of prior anti-myeloma treatments including an immunomodulating agent (IMID) a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody.
    • Participants with a history of autologous stem cell transplant are eligible for study participation when, transplant was >100 days prior to study enrolment and with no active infection(s).
    • Participants with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, unless ECOG less than equal to (<=)2 is due solely to skeletal complications and/or skeletal pain due to MM.
    • Participants with measurable disease defined as at least one of the following: Serum M-protein greater than equal to (>=)0.5 gram per deciliter (>=5 gram per liter) or Urine M-protein >=200 milligrams (mg) per 24 hours or Serum free light chain (FLC) assay: Involved FLC level >=10 mg per deciliter (>=100 mg per Liter) and an abnormal serum FLC ratio (<0.26 or >1.65).
    • Participants who have tested positive for Hepatitis B core antibody (HBcAb) can be enrolled if the following criteria are met: Serology result HBcAb+, Hepatitis B surface antigen (HBsAg)-; HBV deoxyribonucleic acid (DNA) undetectable during screening.
    • Participants who are currently receiving physiological doses oral steroids (<10 mg/day), inhaled steroids or ophthalmalogical steroids.
    • Inclusion Criteria Specific to Sub-study 6,7, and 8:
    • Participants with contraception requirements specific to Sub-study 6, 7, and 8 respectively.
    • Participants with platelets value for Adequate Organ System Function is ≥75 × 10^9/L.
    • Inclusion Criteria Specific to Sub-study 8:
    • - In Japan, participants should reside in Japan and be Japanese as defined by having all biological Japanese grandparents. Similarly, in China, subjects should reside in China and be Chinese as defined by having all biological Chinese grandparents.
    • - Subjects aged 18 years or older at the time of signing the informed consent form.
    • - Subjects with a histologically or cytologically confirmed diagnosis of MM according to the International Myeloma Working Group (IMWG) diagnostic criteria.
    • - Subjects with a history of ≥3 lines of anti-myeloma therapy including immunomodulatory agents (IMIDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies.
    • - Subjects with a history of autologous hematopoietic stem cell transplantation are eligible to participate in this study if the transplant was performed >100 days prior to screening and they have no active infections.
    • - Subjects with an ECOG Performance Status (PS) of 0-1, except for those with an ECOG PS of ≤2 solely due to skeletal complications and/or bone pain due to MM.
    • - Subjects with measurable lesions meeting one or more of the following criteria: Serum M protein ≥0.5g/dL (≥5g/L), urinary M protein ≥200mg/24 hours, serum free light chain (FLC) measurement: involved FLC value ≥10mg/dL (≥100mg/L) and abnormal serum FLC ratio (<0.26 or >1.65).
    • ・Hepatitis B core antibody (HBcAb) positive subjects can participate if they meet the following criteria: serological test results are HBcAb+, hepatitis B surface antigen (HBsAg)-, and HBV DNA is undetectable by screening test.
    • ・Current treatment with physiological doses of oral steroids (<10mg/day), inhaled steroids, or ophthalmic steroids is acceptable.
    Exclusion criteria
    • Participants with current corneal epithelial disease except mild punctate keratopathy.
    • Participants with evidence of cardiovascular risk.
    • Participants with known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other mAb.
    • Participants with active infection requiring antibiotic, antiviral, or antifungal treatment.
    • Participants with other monoclonal antibodies within 30 days or systemic anti-myeloma therapy within <14 days.
    • Participants with prior radiotherapy within 2 weeks of start of study therapy.
    • Participants with prior allogeneic transplant are prohibited.
    • Participants who have received prior Chimeric Antigen T cell therapy (CAR-T) therapy with lymphodepletion with chemotherapy within 3 months of screening.
    • Participants with any major surgery (other than bone-stabilizing surgery) within the last 30 days.
    • Participants with prior treatment with an investigational agent within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is shorter.
    • Participants with >=grade 3 toxicity considered related to prior check-point inhibitors and that led to treatment discontinuation.
    • Participants who have received transfusion of blood products within 2 weeks before the first dose of study drug.
    • Participants must not receive live attenuated vaccines within 30 days prior to first dose of study treatment or whilst receiving belantamab mafodotin +- partner agent in any sub-study arm of the platform trial and for at least 70 days following last study treatment.
    • Participants with presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM.
    • Participants with known human immunodeficiency virus (HIV) infection, unless the participant can meet all criteria: a) established anti-retroviral therapy for at least 4 weeks and HIV viral load<400 copies/milliliter (mL) b) cluster of differentiation 4 plus (CD4+) T-cell (CD4+) counts >= 350 cells/microliter (µL) c) No history of Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months in which case the participant would be eligible for CE Phase only.
    • For participants receiving nirogacestat, HIV drugs that are strong Cytochrome P450 3A4 (CYP3A4) inhibitors are prohibited. HIV drugs that are moderate CYP3A4 inhibitors, while permitted, should be co-administered with caution and must be accompanied by nirogacestat dose modifications.
    • Additional Exclusion Criteria for Sub-study 1 and 2:
    • Participants with autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years.
    • Exclusion for a recent (within the past 6 months) history of symptomatic pericarditis.
    • Additional Exclusion Criteria for Sub-study 3, 6, 7, and 8:
    • Participants with uncontrolled small and/or large intestinal disease.
    • Participants with uncontrolled skin disease.
    • Participants with any condition causing hypophosphatemia, hypokalemia or hypomagnesemia which is refractory to electrolyte replacement.
    • Participants with previous administration of a gamma secretase inhibitor.
    • Participants with concomitant administration of a strong CYP3A4 inhibitor or inducer.
    • Additional Exclusion Criteria for Sub-study 4:
    • Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
    • Participants who have received prior therapy with an anti-programmed death-1 (anti-PD-1), anti-PD-1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent.
    • Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Use of inhaled steroids, local injection of steroids, and steroid eye drops are allowed.
    • Additional Exclusion Criteria for Sub-study 5:
    • Participants with Severe hypersensitivity to Isatuximab-irfc or to any of its excipients.
    • Participants with prior treatment with other anti-CD38 monoclonal antibody within 6 months of the first dose of study drug treatment.
    • Participants with known intolerance or hypersensitivity to infused proteins products, sucrose, histidine, and polysorbate 80.
    • Additional Exclusion Criteria for Sub-study 6, 7, and 8:
    • Participants with active or history of venous thromboembolism within the past 3 months.
    • Participants with evidence of active mucosal or internal bleeding.
    • Participants with contraindications to or are unwilling to undergo protocol-required anti-thrombotic prophylaxis or unable to tolerate antithrombolitic prophalaxis.
    • Additional Exclusion Criteria for Sub-study 6 and 8:
    • - Participants who discontinued prior treatment with lenalidomide due to intolerable adverse events.
    • Additional Exclusion Criteria for Sub-study 7:
    • - Participants who discontinued prior treatment with pomalidomide due to intolerable adverse events.
    • Additional Exclusion Criteria for Sub-study 8:
    • Pregnant or lactating female or female who are interrupting lactation.
    • Previously diagnosed with interstitial lung disease or current complication of interstitial lung disease.
    • -Subjects with current corneal epithelial disease other than mild punctate keratopathy.
    • -Subjects with cardiovascular risk. -Subjects
    • with known immediate or delayed hypersensitivity reactions or idiosyncrasies to drugs chemically related to belantamab mafodotin or any of the components of the concomitant treatment. -Subjects with a history of severe hypersensitivity to other mAbs. -Subjects with active infections requiring treatment with antibacterial, antiviral, or antifungal agents. -Subjects
    • who have received treatment
    • with other monoclonal antibodies within 30 days prior to the first dose of study drug or systemic therapy for myeloma within 14 days prior to the first dose of study drug. -Subjects who have received
    • radiation therapy within 2 weeks prior to the first dose of study drug.
    • -Subjects with a history of allogeneic transplant.
    • -Subjects who have received CAR-T therapy with lymphodepleting chemotherapy within 3 months prior to screening.
    • -Subjects who have received major surgery (other than bone stabilization surgery) within 30 days prior to the first dose of study drug.
    • -Subjects who have used any investigational drug within 14 days or 5 half-lives (whichever is shorter) prior to their first dose of investigational drug.
    • -Subjects who have had grade 3 or higher toxicity considered related to a previous checkpoint inhibitor, leading to treatment discontinuation.
    • -Subjects who have received a blood product transfusion within 2 weeks prior to their first dose of investigational drug. -Subjects
    • cannot have received attenuated vaccines within 30 days prior to their first dose of investigational drug, or during treatment with belantamab mafodotin ± combination therapy, and for at least 70 days after the last dose of investigational drug.
    • -Subjects with active renal disease (diseases that may affect the subject's safety, such as infections or the need for dialysis). Subjects with isolated proteinuria due to MM.

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Midwest
    Grand Rapids, MI, United States, 49546
    Investigator
    Nehal Lakhani
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Multiple Myeloma